Hemostatic devices and methods of making same

ABSTRACT

The present invention includes compositions suitable for use in a hemostatic device and hemostatic devices utilizing such compositions, as well as methods of making the compositions and the medical devices utilizing such compositions, where the compositions contain biocompatible, oxidized cellulose particles having an average designated nominal particle size of about 0.035-4.35 mm and a biocompatible, water-soluble or water-swellable polysaccharide porous binder component.

FIELD OF THE INVENTION

[0001] The present invention relates to compositions suitable for use inhemostatic devices, hemostatic devices utilizing such compositions andmethods of making such compositions and hemostatic devices.

BACKGROUND OF THE INVENTION

[0002] The control of bleeding is essential and critical in surgicalprocedures to minimize blood loss, to reduce post-surgicalcomplications, and to shorten the duration of the surgery in theoperating room. Due to its biodegradability and its bactericidal andhemostatic properties, cellulose that has been oxidized to containcarboxylic acid moieties, hereinafter referred to as carboxylic-oxidizedcellulose, has long been used as a topical hemostatic wound dressing ina variety of surgical procedures, including neurosurgery, abdominalsurgery, cardiovascular surgery, thoracic surgery, head and necksurgery, pelvic surgery and skin and subcutaneous tissue procedures.

[0003] Currently utilized hemostatic wound dressings include knitted ornon-woven fabrics comprising carboxylic-oxidized cellulose. Currentlyutilized oxidized cellulose is carboxylic-oxidized regenerated cellulosecomprising reactive carboxylic acid groups and which has been treated toincrease homogeneity of the cellulose fiber. Examples of such hemostaticwound dressings commercially available include Surgicel® absorbablehemostat; Surgicel Nu-Knit® absorbable hemostat; and Surgicel® Fibrillarabsorbable hemostat; all available from Johnson & Johnson WoundManagement Worldwide, a division of Ethicon, Inc., Somerville, N.J., aJohnson & Johnson Company. Other examples of commercial absorbablehemostats containing carboxylic-oxidized cellulose include Oxycel®absorbable cellulose surgical dressing from Becton Dickinson andCompany, Morris Plains, N.J., and Curacel® oxidized regeneratedcellulose powder from Curaspon Healthcare, the Netherlands.

[0004] Hemostatic devices utilizing carboxylic-oxidized cellulose, dueto its acidic pH, are known to rapidly denature acid-sensitive,hemostatic proteins, including thrombin or fibrinogen, on contact. Thus,it is problematic to use the carboxylic-oxidized cellulose as a carrierfor acid-sensitive species, such as thrombin and fibrinogen, as well asother acid-sensitive biologics and pharmaceutical agents.

[0005] In addition to issues concerning compatibility of conventionalcarboxylic-oxidized cellulose with “acid-sensitive” species, e.g.proteins, drugs, etc., while the absorbency of body fluid and thehemostatic action of such currently available carboxylic-oxidizedcellulose hemostats are adequate for applications where mild to moderatebleeding is encountered, they are not known to be effective to provideand maintain hemostasis in cases of severe bleeding where a relativelyhigh volume of blood is lost at a relatively high rate. In suchinstances, e.g. arterial puncture, liver resection, blunt liver trauma,blunt spleen trauma, aortic aneurysm, bleeding from patients withover-anticoagulation, or patients with coagulopathies, such ashemophilia, etc., a higher degree of hemostasis is required quickly.

[0006] The present invention provides devices that provide hemostaticand anti-microbial properties equivalent to or better than conventionalhemostatic devices or that also may be compatible with “acid-sensitive”species, and methods for preparing such devices.

SUMMARY OF THE INVENTION

[0007] The present invention is directed to compositions suitable foruse in a hemostatic device and hemostatic devices utilizing suchcompositions, where the compositions comprise biocompatible, oxidizedcellulose particles having an average designated nominal particle sizeof about 0.035-4.35 mm; and a biocompatible, water-soluble orwater-swellable polysaccharide porous binder component. The inventionalso is directed to methods of making the compositions and the medicaldevices utilizing such compositions.

BRIEF DESCRIPTION OF THE FIGURES

[0008]FIG. 1 is a scanning electron microscopy image (X50) of a crosssection of a wound dressing described in example 1c

[0009]FIG. 2a is a scanning electron microscopy image (X50) of the firstsurface of a wound dressing described in example 1c.

[0010]FIG. 2b is a scanning electron microscopy image (X250) of thefirst surface of a wound dressing described in example 1c.

[0011]FIG. 3a is a scanning electron microscopy image (X50) of thesecond opposing surface of a wound dressing described in example 1c.

[0012]FIG. 3b is a scanning electron microscopy image (X250) of thesecond opposing surface of a wound dressing described in example 1c.

[0013]FIG. 4 is a scanning electron microscopy image (X50) of a crosssection of a wound dressing described in example 1b

[0014]FIG. 5a is a scanning electron microscopy image (X50) of the firstsurface of a wound dressing described in example 1b.

[0015]FIG. 5b is a scanning electron microscopy image (X250) of thefirst surface of a wound dressing described in example 1b.

[0016]FIG. 6a is a scanning electron microscopy image (X50) of thesecond opposing surface of a wound dressing described in example 1b.

[0017]FIG. 6b is a scanning electron microscopy image (X250) of thesecond opposing surface of a wound dressing described in example 1b.

[0018]FIG. 7 is a scanning electron microscopy image (X50) of a crosssection of a wound dressing described in Example 1a.

[0019]FIG. 8a is a scanning electron microscopy image (X50) of the firstsurface of a wound dressing described in example 1a.

[0020]FIG. 8b is a scanning electron microscopy image (X250) of thefirst surface of a wound dressing described in example 1a.

[0021]FIG. 9a is a scanning electron microscopy image (X50) of thesecond opposing surface of a wound dressing described in example 1a.

[0022]FIG. 9b is a scanning electron microscopy image (X250) of thesecond opposing surface of a wound dressing described in example 1a.

[0023]FIG. 10a is a scanning electron microscopy image (X50) of a crosssection of a hemostatic device described in example 3.

[0024]FIG. 10b is a scanning electron microscopy image (X250) of a crosssection of a hemostatic device described in example 3.

[0025]FIG. 11a is a scanning electron microscopy image (X50) of asurface morphology of a hemostatic device described in example 3.

[0026]FIG. 11b is a scanning electron microscopy image (X250) of asurface morphology of a hemostatic device described in example 3.

[0027]FIG. 12a is a scanning electron microscopy image (X50) of anagglomerate described in example 4.

[0028]FIG. 12b is a scanning electron microscopy image (X250) of anagglomerate described in example 4.

[0029]FIG. 13 is a scanning electron microscopy image (X50) of a surfacemorphology of the micro-fibers described in example 2.

DETAILED DESCRIPTION OF THE INVENTION

[0030] We have discovered certain compositions that utilizebiocompatible oxidized cellulose particles and a biocompatible, porouspolysaccharide binder component and that possess properties suitable foruse in hemostatic devices. Particles, as used herein, is meant toinclude various forms of solid particulate material that may be combinedwith a polymeric binder component to form a composition havingstructure, and specifically includes forms such as fibers and powders ofboth regular and irregular shape. The compositions comprise a porous,polymer binder component, whereby the oxidized cellulose particles arebound by the binder component so as to provide the composition withphysical and chemical properties suitable for use in hemostatic devices.The physical structure of the compositions may be in the form of a foamor an agglomerate, each as described in more detail herein below.

[0031] Hemostatic devices of the present invention utilizing suchcompositions provide and maintain effective hemostasis when applied to awound requiring hemostasis. Effective hemostasis, as used herein, is theability to control and/or abate capillary, venous, or arteriole bleedingwithin an effective time, as recognized by those skilled in the art ofhemostasis. Further indications of effective hemostasis may be providedby governmental regulatory standards and the like.

[0032] In certain embodiments, hemostatic devices of the presentinvention may be effective in providing and maintaining hemostasis incases of severe bleeding. As used herein, severe bleeding is meant toinclude those cases of bleeding where a relatively high volume of bloodis lost at a relatively high rate. Examples of severe bleeding include,without limitation, bleeding due to arterial puncture, liver resection,blunt liver trauma, blunt spleen trauma, aortic aneurysm, bleeding frompatients with over-anticoagulation, or bleeding from patients withcoagulopathies, such as hemophilia. Such devices allow a patient toambulate quicker than the current standard of care following, e.g. adiagnostic or interventional endovascular procedure.

[0033] The polymer used to prepare the porous, binder component incompositions and devices of the present invention is a biocompatible,water-soluble, or water-swellable polymer. In order to provide thecomposition with chemical properties suitable for use in hemostaticdevices, the water-soluble or water-swellable polymer must rapidlyabsorb blood or other body fluids and form a tacky or sticky gel adheredto tissue when placed in contact therewith. The fluid-absorbing polymer,when in a dry or concentrated state, interacts with body fluid through ahydration process. Once applied to a bleeding site, the polymerinteracts with the water component in the blood via the hydrationprocess. The hydration force not only provides an adhesive interactionthat aids in the hemostatic device adhering to the bleeding site, but italso serves as a sealant at the bleeding site to stop the blood flow andthus aid in hemostatis provided by the oxidized cellulose fibers.

[0034] Preferred polymers used as a binder component includepolysaccharides. Such polysaccharides include, without limitation,cellulose, alkyl cellulose, e.g. methylcellulose, alkylhydroxyalkylcellulose, hydroxyalkyl cellulose, cellulose sulfate, salts ofcarboxymethyl cellulose, carboxymethyl cellulose, carboxyethylcellulose, chitin, carboxymethyl chitin, hyaluronic acid, salts ofhyaluronic acid, alginate, alginic acid, propylene glycol alginate,glycogen, dextran, dextran sulfate, curdlan, pectin, pullulan, xanthan,chondroitin, chondroitin sulfates, carboxymethyl dextran, carboxymethylchitosan, chitosan, heparin, heparin sulfate, heparan, heparan sulfate,dermatan sulfate, keratan sulfate, carrageenans, chitosan, starch,amylose, amylopectin, poly-N-glucosarnine, polymannuronic acid,polyglucuronic acid polyguluronic acid, and derivatives of any of theabove.

[0035] Preferably, oxidized cellulose particles are used to prepare thecompositions and hemostatic devices of the present invention. Theoxidized cellulose may be amorphous, crystalline or a combinationthereof. The oxidized cellulose may be carboxylic-oxidized cellulose oraldehyde-oxidized cellulose, each as defined and described herein. Theoxidized cellulose may be oxidized regenerated cellulose, which has ahigher degree of uniformity versus cellulose that has not beenregenerated. Regenerated cellulose and a detailed description of how tomake oxidized regenerated cellulose is set forth in U.S. Pat. No.3,364,200, which discloses the preparation of carboxylic-oxidizedcellulose with an oxidizing agent such as dinitrogen tetroxide in aFreon medium, and U.S. Pat. No. 5,180,398, which discloses thepreparation of carboxylic-oxidized cellulose with an oxidizing agentsuch as nitrogen dioxide in a per-fluorocarbon solvent, the contentseach of which is hereby incorporated by reference as if set forth in itsentirety. After oxidation by either method, the carboxylic-oxidizedcellulose is thoroughly washed with a solvent such as carbontetrachloride, followed by aqueous solution of 50 percent isopropylalcohol (IPA), and finally with 99% IPA. As such, teachings concerningoxidized regenerated cellulose and methods of making same are wellwithin the knowledge of one skilled in the art of hemostatic devices.

[0036] Oxidized cellulose particles may be derived from an oxidizedcellulose fabric that is woven or non-woven. Exemplary fabrics aredescribed in U.S. Pat. No. 4,626,253, the contents of which is herebyincorporated by reference herein as if set forth in its entirety. Theoxidized cellulose particles may be obtained from fabrics utilized inconventional hemostatic wound dressings, such as Surgicel® absorbablehemostat; Surgicel Nu-Knit® absorbable hemostat; and Surgicel® Fibrillarabsorbable hemostat; all available from Johnson & Johnson WoundManagement Worldwide, a division of Ethicon, Inc., Somerville, N.J., aJohnson & Johnson Company, as well as Oxycel® absorbable cellulosesurgical dressing from Becton Dickinson and Company, Morris Plains, N.J.Oxidized cellulose powder such as Curacel® oxidized regeneratedcellulose powder from Curaspon Healthcare, the Netherlands, also may beused in compositions and hemostatic devices of the present invention.

[0037] Embodiments of the present invention include the use of oxidizedcellulose particles that are derived from absorbable hemostatic fabricsthat are warp knitted tricot fabrics constructed of bright rayon yarnwhich is subsequently oxidized to include carboxyl or aldehyde moietiesin amounts effective to provide the fabrics with biodegradability andanti-microbial activity. The fabrics are characterized by having asingle ply thickness of at least about 0.5 mm, a density of at leastabout 0.03 g/cm², air porosity of less than about 150 cm³/sec/cm², andliquid absorption capacity of at least about 3 times the dry weight ofthe fabric and at least about 0.1 g water per cm² of the fabric.

[0038] The tricot fabrics from which the oxidized cellulose particlesmay be derived may be constructed from bright rayon yarns of from about40 to 80 total denier. Each yarn may contain from 10 to 25 individualfilaments, although each individual filament preferably is less than 5denier to avoid extended absorption times. The high bulk and fabricdensity are obtained by knitting at 28 gauge or finer, preferably at 32gauge, with a fabric quality of about 10 or 12 (40 to 48 courses perinch). A long guide bar shog movement of at least 6 needle spaces, andpreferably 8 to 12 spaces, further increases fabric thickness anddensity.

[0039] Where the oxidized cellulose is a carboxylic-oxidized cellulose,the oxidized cellulose may be conditioned prior to use. Conditioning canbe achieved by storing the oxidized cellulose at room temperature underambient conditions for at least 6 month, or conditioning can beaccelerated. Alternatively, the oxidized cellulose is exposed toconditions of about 4° C. to about 90° C., at a relative humidity offrom about 5% to about 90%, for a time of from about 1 hour to 48months; conditions of about 4° C. to about 60° C., at a relativehumidity of from about 30% to about 90%, for a time of from about 72hours to 48 months; conditions of about 18° C. to about 50° C., at arelative humidity of from about 60% to about 80%, for a time of fromabout 72 hours to 366 hours; or conditions of about 50° C., at arelative humidity of about 70%, for a time of about 168 hours.

[0040] As a result of the conditioning, the carboxylic-oxidizedcellulose particles will comprise at least about 3 weight percent ofwater-soluble molecules, preferably from about 3 to about 30 weightpercent, more preferably from about 8 to about 20 weight percent, evenmore preferably from about 9 to about 12 weight percent, and mostpreferably about 10 weight percent. In general, the water-solublemolecules are acid-substituted oligosaccharides containing approximately5 or fewer saccharide rings. It has been found that the hemostaticefficacy of a wound dressing derived from such carboxylic-oxidizedcellulose, including the occurrence of re-bleeding of a wound for whichhemostasis initially has been achieved, is improved when the contents ofthe water-soluble molecules reach about 8%, preferably about 10%, basedon the weight of the carboxylic-oxidized cellulose.

[0041] The oxidized cellulose particles also will comprise from about 3to about 20 weight percent of water, preferably from about 7 to about 13weight percent, and more preferably from about 9 to about 12 weightpercent water prior to use. Similar levels of moisture and water-solublemolecules in the carboxylic-oxidized cellulose also may be achieved byother means. For example, sterilization by known techniques, such asgamma or e-beam irradiation, may provide similar content of water and/orwater-soluble molecules. In addition, water-soluble molecules such asoligosacchrides could be added to the oxidized cellulose particles priorto use. Once having the benefit of this disclosure, those skilled in theart may readily ascertain other methods for providing such oxidizedcelluloses with moisture and/or water-soluble molecules.

[0042] In some embodiments of the invention, hemostatic agents, or otherbiological or therapeutic compounds, moieties or species, e.g. drugs,and pharmaceutical agents, may be used. As discussed above, such agentsor compounds may be “acid-sensitive”, meaning that they may be degradedor denatured by, or otherwise detrimentally affected by acidic pH, suchas is provided by conventional carboxylic-oxidized hemostatic wounddressings. Hemostatic devices of the present invention that arecompatible with acid-sensitive species comprise oxidized cellulosederived from a biocompatible, aldehyde-oxidized polysaccharide. In suchdevices, the polysaccharide preferably will contain an amount ofaldehyde moieties effective to render the modified polysaccharidebiodegradable, meaning that the polysaccharide is degradable by the bodyinto components that either are resorbable by the body, or that can bepassed readily by the body. More particularly, the biodegradedcomponents do not elicit permanent chronic foreign body reaction whenthey are absorbed by the body, such that no permanent trace or residualof the component is retained at the implantation site.

[0043] Aldehyde-oxidized polysaccharides used in the present inventionmay include, without limitation, cellulose, cellulose derivatives, e.g.alkyl cellulose, for instance methyl cellulose, hydroxyalkyl cellulose,alkylhydroxyalkyl cellulose, cellulose sulfate, salts of carboxymethylcellulose, carboxymethyl cellulose and carboxyethyl cellulose, chitin,carboxymethyl chitin, hyaluronic acid, salts of hyaluronic acid,alginate, alginic acid, propylene glycol alginate, glycogen, dextran,dextran sulfate, curdlan, pectin, pullulan, xanthan, chondroitin,chondroitin sulfates, carboxymethyl dextran, carboxymethyl chitosan,heparin, heparin sulfate, heparan, heparan sulfate, dermatan sulfate,keratin sulfate, carrageenans, chitosan, starch, amylose, amylopectin,poly-N-glucosamine, polymannuronic acid, polyglucuronic acid,polyguluronic acid and derivatives of the above, each of which has beenoxidized to included anti-microbial effective amounts of aldehydemoieties.

[0044] In preferred embodiments utilizing aldehyde-oxidizedpolysaccharides, the polysaccharide is oxidized as described herein toassure that the aldehyde-oxidized polysaccharide is biodegradable. Suchbiodegradable, aldehyde-oxidized polysaccharides may be represented byStructure I below.

[0045] where x and y represent mole percent, x plus y equals 100percent, x is from about 95 to about 5, y is from about 5 to about 95;and R may be CH₂OR₃, COOR₄, sulphonic acid, or phosphonic acid; R₃ andR₄ may be H, alkyl, aryl, alkoxy or aryloxy, and R₁ and R₂ may be H,alkyl, aryl, alkoxy, aryloxy, sulphonyl or phosphoryl.

[0046] In certain embodiments of the present invention, thebiocompatible, biodegradable hemostatic devices comprises biocompatible,biodegradable, aldehyde-oxidized regenerated cellulose. In particular,preferred aldehyde-oxidized regenerated cellulose is one comprisingrepeating units of Structure II:

[0047] where x and y represent mole percent, x plus y equals 100percent, x is from about 95 to about 5, y is from about 5 to about 95;and R is CH₂OH, R₁ and R₂ are H.

[0048] In preferred embodiments of the invention, the aldehyde-oxidizedregenerated polysaccharide, e.g. cellulose, is essentially free offunctional or reactive moieties other than aldehyde moieties. Byessentially free, it is meant that the polysaccharide does not containsuch functional or reactive moieties in amounts effective to alter theproperties of the aldehyde-oxidized polysaccharide, or to provide thepolysaccharide with a pH of less than about 4.5, more preferably lessthan about 5, or greater than about 9, preferably about 9.5. Suchmoieties include, without limitation, carboxylic acid moieties typicallypresent in wound dressings made from carboxyl-oxidized cellulose. Excesslevels of carboxylic acid moieties will lower the pH of the dressings sothat they are not compatible for use with those acid-sensitive speciesthat may be degraded or denatured by such a low pH, e.g. thrombin. Othermoieties essentially excluded include, without limitation, sulfonyl orphosphonyl moieties.

[0049] Generally, the oxidized cellulose particles of the presentinvention have an average designated nominal particle size of betweenabout 0.035 mm (Tyler mesh size 400) to about 4.35 mm (Tyler mesh size5). More preferably, the oxidized cellulose has an average designatednominal particle size of about 0.68 mm to about 4.35 mm. Mostpreferably, the oxidized cellulose particles have an average designatednominal particle size of from about 0.80 to about 2.20 mm (Tyler meshsize ranging from 10 to 20). By designated nominal particle size, wemean a mean distribution of a certain particle size with permissiblevariation range, as defined in ASTM E11-87.

[0050] Oxidized cellulose particles used in the present inventionpreferably have an average designated nominal particle size ranging fromabout 0.68 mm to about 4.35 mm. The oxidized cellulose particles used inthe present invention may be made by chopping the hemostatic fabricsdescribed above or any oxidized cellulose fabric with a cutting blade ofa motor-driven mill to the desired fiber length using an Thomas-Wiley®Laboratory Mill, Intermediate Model cutting blade. The motor-drivenmill, with two stationary blades and a motor with four cutting edgesrevolving at high speed to produce a shearing action, is ideal for rapidmilling of fabric samples. For example, the oxidized cellulose particlesmay be made by placing an oxidized cellulose fabric, such as Surgicel®absorbable hemostat; Surgicel Nu-Knit® absorbable hemostat; or Surgicel®Fibrillar absorbable hemostat, or an oxidized cellulose, in a stainlesssteel foil pouch filled with liquid nitrogen and submerging the foilpouch in liquid nitrogen. The foil pouch is then passed through a dualwheel roller at, for example, 6 in/min, yielding oxidized cellulosehaving an average particle size of 0.035-4.35 mm.

[0051] The compositions used to make the hemostatic devices of thepresent invention may be made by first dissolving the water-soluble orwater-swellable polymer in water to make a polymer solution. Theoxidized cellulose particles, e.g. fibers, and the polymer solution maythen be homogenized using an Ultra-TURRAX® T18 DIXI midiDispersers/Homogenizers to aid the dispersion of particles throughoutthe solution. The homogenizer, with its mechanical action, is known foruse in blending unlike materials to make a homogenous distribution.After the oxidized cellulose particles are dispersed in the polymersolution, the dispersion is subjected to conditions under which thedissolved water-soluble or water-swellable polymer is solidified so asto provide a porous binder component for the oxidized celluloseparticles. The solvent, i.e. water, then is extracted from thecomposition to yield a porous composition comprising the oxidizedcellulose particles of desired size and the porous polymeric bindercomponent.

[0052] Depending on the conditions to which the homogenous dispersion issubjected, the compositions may be in various forms. For example, thecompositions may be in the form of a porous foam, whereby the oxidizedcellulose particles are dispersed in a porous foam binder component toform a porous foam sponge, as depicted in FIGS. 1 thru 9 b and asdescribed in Examples 1a-1c; or to form porous foam beads as depicted inFIGS. 10a thru 11 b and as described in Example 3, depending on themethods used to prepare the composition. In such cases, the particlesmay be bound within the structure of the porous foam binder componentwhere they may provide hemostatic properties to the composition. At thesame time, the porous nature of the polymeric binder component allowsgreater exposure of the binder to water within the body. Thecompositions also may take the form of a porous agglomerate of particlesand polymer binder, as depicted in FIGS. 12a and 12 b and as describedin Example 4. In such a case, the porous polymeric binder component maytake on a more fibrous structure that is intertwined with the oxidizedcellulose particles, as opposed to a foam structure of the sponge orbeads. Again, the porous nature of the agglomerates, due in part to thefibrous structure of the binder component, permits greater exposure ofthe polymer binder to the water in the body. In both cases, the surfacearea of the binder is maximized so as to provide faster and moreextensive hydration by water in the body, which in turn leads to fasterand more extensive sealing properties to aid in the hemostaticproperties of the oxidized cellulose particles. Such compositions may befurther processed into various hemostatic devices.

[0053] One method of making the porous foam sponge composition used tomake hemostatic devices of the present invention is to dissolve thewater-soluble or water-swellable polymer in an appropriate solvent forthe polymer to prepare a homogenous polymer solution; contact theoxidized cellulose particles with an appropriate amount of the polymersolution by homogenization, such that the oxidized cellulose particlesare dispersed in the polymer solution; and then flash-freeze the polymersolution having the particles and dry/remove the solvent from the frozenstructure by, for example, lyophilization at a pressure rangingpreferably from 0-250 mtorr, more preferably from 0-200 mtorr, at atemperature ranging from 0° C. to −50° C., for a time duration rangingfrom 10-14 hours. Lyophilization removes the solvent by sublimation,leaving a porous foam sponge having the oxidized cellulose particlesdispersed throughout the porous foam binder component.

[0054] During the lyophilization process, several parameters andprocedures are important to produce compositions having mechanicalproperties suitable for use in hemostatic devices. The type ofmicroporous morphology developed during the lyophilization is a functionof several factors, such as the solution thermodynamics, freezing rate,temperature to which it is frozen, and concentration of the solution. Tomaximize the surface area of the porous foam beads of the presentinvention, the homogenized polymer solution/particles may first bequickly frozen at lower than 0° C., preferably at about −50° C., i.e. bydripping into liquid nitrogen, followed by removal of the solvent at apressure ranging preferably from 0-250 mtorr, more preferably from 0-200mtorr, at a temperature ranging from 0° C. to −50° C., for a timeduration ranging from 10-14 hours; leaving porous foam beads having theoxidized cellulose particles dispersed throughout the porous foam bindercomponent.

[0055] One method of making the porous fibrous agglomerates that may beused to make hemostatic devices of the present invention is to dissolvethe water-soluble or water-swellable polymer in an appropriate solventfor the polymer to prepare a homogenous polymer solution; contact theoxidized cellulose particles with an appropriate amount of the polymersolution by homogenization, such that the oxidized cellulose particlesare dispersed in the polymer solution; dripping the homogenizeddispersion into isopropanol to precipitate the water-soluble orwater-swellable polymer and to form fibrous agglomerates having oxidizedcellulose dispersed therein, and then flash-freeze and dry/remove thesolvent from the fibrous agglomerates by, for example, lyophilization ata pressure ranging preferably from 0-250 mtorr, more preferably from0-200 mtorr, at a temperature ranging from 0° C. to −50° C., for a timeduration ranging from 10-14 hours, leaving porous agglomerates havingthe oxidized cellulose particles dispersed throughout a fibrousstructure of porous polymeric binder component.

[0056] If the ratio of the water-soluble or water-swellable polymer tooxidized cellulose particles is too low, the polymer does not provide aneffective seal to physically block the bleeding, thus reducing thehemostatic properties. If the ratio is too high, the hemostat devicewill be too stiff or too brittle to conform to wound tissue in surgicalapplications, thus adversely affecting the mechanical propertiesnecessary for handling by the physician in placement and manipulation ofthe device. A preferred weight ratio of polymer to oxidized cellulose isfrom about 1:99 to about 15:85. A more preferred weight ratio of polymerto oxidized cellulose is from about 3:97 to about 10:90.

[0057] As discussed above, hemostatic devices utilizing the compositionsso produced may be of various forms. When the composition is in the formof a porous foam sponge, its thickness is preferably greater than 2.0mm. More preferably, the thickness of the sponge ranges from 2.0 to 10mm. Most preferably, the thickness of the sponge ranges from 2.5 to 5.5mm, and the average designated nominal particle size of the oxidizedcellulose particles is from about 0.80 mm to about 2.2 mm. A hemostaticdevice utilizing this composition remains very flexible, conforms to ableeding site and retains good tensile and compressive strength towithstand handling during application. The hemostatic device can be cutinto different sizes and shapes to fit the surgical needs, or can berolled up or packed into irregular anatomic areas or to facilitate usein endoscopic/less invasive procedures.

[0058] In addition, non-woven hemostatic devices may be prepared bycompacting the porous foam beads or fibrous agglomerates such as may bepracticed in producing non-woven felt fabrics. Foam beads or fibrousagglomerates may be made to such a size as to permit the formation ofpastes or slurries comprising the beads or agglomerates, whereby thepastes or slurries may be applied to or injected into areas requiringhemostatsis. Such pastes and slurries are reported in the art and oncehaving the benefit of this disclosure those skilled in the art wouldreadily be able to prepare such devices. Other embodiments of hemostaticdevices contemplated by the inventions include a hemostatic powder, ahemostatic patch, or a hemostatic plug whereby beads or agglomerates arecompressed or formulated with excipients.

[0059] As noted above, in certain embodiments of the invention, ahemostatic agent, a biologic or therapeutic compounds, such as drugs orpharmaceutical agents, or combinations thereof, that otherwise may besensitive to the low pH of conventional carboxyl-oxidizedcellulose-containing wound dressings, may be incorporated intohemostatic devices of the present invention utilizing analdehyde-oxidized cellulose, without having to adjust pH prior toincorporation into the dressing. Moreover, protein-based hemostaticagents, such as thrombin, fibrin or fibrinogen, if bound to thehemostatic device, can enhance the hemostatic property ofaldehyde-oxidized cellulose hemostatic device and reduce the risk ofthrombosis caused by free hemostatic agents migrating into the bloodstream. Hemostatic agents may be bound to the hemostatic device eitherby chemical of physical means. Agents may be covalently conjugated withaldehyde groups pendant from the polysaccharide in one instance, thuschemically binding the agent to the hemostatic device. Preferably, thehemostatic agents are physically bound to the hemostatic device viaincorporation into the polymer and immobilized, i.e. bound, vialyophilization.

[0060] Hemostatic devices made from an aldehye-oxidized cellulose maycomprise hemostatic agents, including but not limited to thrombin,fibrinogen or fibrin, in an amount effective to provide rapid hemostasisand maintain effective hemostasis in cases of severe bleeding. If theconcentration of the hemostatic agent in the wound dressing is too low,the hemostatic agent does not provide an effective proagulant activityto promote rapid clot formation upon contact with blood or blood plasma.A preferred concentration range of thrombin in the hemostatic device isfrom about 0.001 to about 1 percent by weight. A more preferredconcentration of thrombin in the hemostatic device is from about 0.01 toabout 0.1 percent by weight. A preferred concentration range offibrinogen in the hemostatic device is from about 0.1 to about 50percent by weight. A more preferred concentration of fibrinogen in thehemostatic device is from about 2.5 to about 10 by weight. A preferredconcentration range of fibrin in the hemostatic device is from about 0.1to about 50 percent by weight. A more preferred concentration of fibrinin the hemostatic device is from about 2.5 to about 10 by weight.

[0061] In certain embodiments, the aldehyde-oxidized cellulose maycomprise covalently conjugated therewith a hemostatic agent bearing analdehyde-reactive moiety. In such embodiments, the aldehyde moiety ofaldehyde-oxidized regenerated cellulose can readily react with the aminegroups present on the amino acid side chains or N-terminal residues ofthrombin, fibrinogen or fibrin, resulting in forming a conjugate of thehemostatic agent with the aldehyde-oxidized regenerated cellulosecovalently linked by a reversible imine bond. The imine bondedaldehyde-oxidized regenerated cellulose/hemostatic agent conjugate maythen be further reacted with a reducing agent such as sodium borohydrideor sodium cyanoborohydride to form an irreversible secondary aminelinkage. In such embodiments of the invention, the hemostatic agent isdispersed at least on the surface of the hemostatic device, andpreferably at least partially through the hemostatic device, boundreversibly or irreversibly to the aldehyde-oxidized cellulose.

[0062] In preferred embodiments of the present invention, the hemostaticagent, such as thrombin, fibrinogen, or fibrin is constituted in anaqueous solution of a non-acidic, water-soluble or water-swellablepolymer, as described herein above, including but not limited to methylcellulose, hydroxyalkyl cellulose, water-soluble chitosan, salts ofcarboxymethyl carboxyethyl cellulose, chitin, salts of hyaluronic acid,alginate, propylene glycol alginate, glycogen, dextran, carrageenans,chitosan, starch, amylose, poly-N-glucosamine, and the aldehyde-oxidizedderivatives thereof. A homogenized suspension of aldehyde-oxidizedcellulose and an aqueous solution of hemostatic agent and thewater-soluble or water-swellable polymer, can be rapidly lyophilizedusing known methods that retain therapeutic activity. When constructedthusly, the hemostatic agent will be substantially homogenouslydispersed through the polymeric substrate formed during lyophilization.

[0063] One skilled in the art, once having the benefit of thisdisclosure, will be able to select the appropriate hemostatic agent,water-soluble or water-swellable polymer and solvent therefore, andlevels of use of both the polymer and hemostatic agent, depending on theparticular circumstances and properties required of the particularhemostatic device.

[0064] Hemostatic devices of the present invention are best exemplifiedin the figures prepared by scanning electron microscope. The sampleswere prepared by cutting 1-cm² sections of the dressings by using arazor. Micrographs of both the first surface and opposing secondsurface, and cross-sections were prepared and mounted on carbon stubsusing carbon paint. The samples were gold-sputtered and examined byscanning electron microscopy (SEM) under high vacuum at 4KV.

[0065] While the following examples demonstrate certain embodiments ofthe invention, they are not to be interpreted as limiting the scope ofthe invention, but rather as contributing to a complete description ofthe invention.

EXAMPLE 1a Chopped CORC Fabric/Na—CMC Porous Patch (10/40) Preparation

[0066] One gram of sodium salt of CMC (Na—CMC, from Aqualon® 7M8SF) wasdissolved in 99 grams of deionized water. After complete dissolution ofthe polymer, 15 grams of the Na—CMC solution was transferred into acrystallization dish with a diameter of 10 cm. A piece of SurgicelNu-Knit® fabric with a diameter of 9.8 cm (about 1.3 gram) was choppedwith a Thomas-Wiley® Laboratory Mill, Intermediate Model cutting bladethen passed through a USA standard Testing Sieve (mesh size=10,A.S.T.M.E.-11 Specification) to yield fibers with an average designatednominal particle size of 1.7 mm. The chopped fabric was placed in theCMC—Na solution in the crystallization dish. The suspension of thechopped fabric in CMC—Na solution was placed in an Ultra-TURRAX® T18DIXI midi Dispersers/Homogenizers homogenizer and homogenized for lessthan 5 min until the loose chopped fabric is evenly distributed in thesolution. The homogeneous solution was then lyophilized in the dishovernight. A very flexible patch was formed (basis weight=40,thickness=5 mm). The patch was further dried at room temperature undervacuum.

EXAMPLE 1b Chopped CORC Fabric/Na—CMC Porous Patch (20/40) Preparation

[0067] One gram of sodium salt of CMC (Na—CMC, from Aqualon® 7M8SF) wasdissolved in 99 grams of deionized water. After complete dissolution ofthe polymer, 15 grams of the Na—CMC solution was transferred into acrystallization dish with a diameter of 10 cm. A piece of SurgicelNu-Knit® fabric with a diameter of 9.8 cm (about 1.3 gram) was choppedwith an Thomas-Wiley® Laboratory Mill, Intermediate Model cutting bladethen passed through a USA standard Testing Sieve (mesh size=20,A.S.T.M.E.-11 Specification) to yield fibers with an average designatednominal particle size of 0.85 mm. The chopped fabric was placed in theCMC—Na solution in the crystallization dish. The suspension of thechopped fabric in CMC—Na solution was placed in an Ultra-TURRAX® T18DIXI midi Dispersers/Homogenizers homogenizer and homogenized for lessthan 5 min until the loose chopped fabric is evenly distributed in thesolution. The homogeneous solution was then lyophilized in the dishovernight. A very flexible patch was formed (basis weight=40,thickness=5 mm). The patch was further dried at room temperature undervacuum.

EXAMPLE 1c Chopped CORC Fabric/Na—CMC Porous Patch (40/40) Preparation

[0068] One gram of sodium salt of CMC (Na—CMC, from Aqualon® 7M8SF) wasdissolved in 99 grams of deionized water. After complete dissolution ofthe polymer, 15 grams of the Na—CMC solution was transferred into acrystallization dish with a diameter of 10 cm. A piece of SurgicelNu-Knit® fabric with a diameter of 9.8 cm (about 1.3 gram) was choppedwith an Thomas-Wiley® Laboratory Mill, Intermediate Model cutting bladethen passed through a USA standard Testing Sieve (mesh size=40,A.S.T.M.E.-11 Specification) to yield fibers with an average designatednominal particle size of 0.43 mm. The chopped fabric was placed in theCMC solution in the crystallization dish. The suspension of the choppedfabric in CMC—Na solution was placed in an Ultra-TURRAX® T18 DIXI midiDispersers/Homogenizers homogenizer and homogenized for less than 5 minuntil the loose chopped fabric is evenly distributed in the solution.The homogeneous solution was then lyophilized in the dish overnight. Avery flexible patch was formed (basis weight=40, thickness=5 mm). Thepatch was further dried at room temperature under vacuum.

EXAMPLE 2 CORC Micro-fibers/Na—CMC Patch Preparation

[0069] CORC Fibrillar was first immersed in liquid nitrogen in astainless steel foil pouch then the LN₂ containing pouch filled withCORC Fibrillar will go through a dual wheel/roller at 6 in/min, yieldingCORC powders, micro fibers or fine particles of various length/sizes.Particles of desired sizes can be subsequently separated with USAstandard Testing Sieves (A.S.T.M.E.-11 Specification) of different meshsizes (20-400), yielding micro-fibers of length ranging from 0.035-0.86mm. CORC particles/powders/micro fibers thus prepared were placed in theCMC—Na solution in the crystallization dish. The suspension of the CORCparticles/powders/micro fibers in CMC—Na solution was placed in anUltra-TURRAX® T18 DIXI midi Dispersers/Homogenizers homogenizer andhomogenized until the loose CORC particles/powders/micro fibers areevenly distributed in the CMC—Na (Aqualon® 7M8SF) solution. Thehomogeneous solution was then lyophilized in the dish overnight. A veryflexible patch was formed (basis weight=40, thickness=5 mm). The patchwas further dried at room temperature under vacuum.

EXAMPLE 3 CORC/Na—CMC Micro-porous Beads Preparation

[0070] CORC Fibrillar is first emerged in liquid nitrogen in a stainlesssteel foil pouch then the LN₂ containing pouch filled with CORCFibrillar will go through a dual wheel/roller at 6 in/min, yielding CORCpowders, micro fibers or fine particles of various length/sizes.Particles of desired sizes can be subsequently separated with sieves.CORC particles/powders/micro fibers thus prepared were placed in theCMC—Na Aqualon® 7M8SF solution in the crystallization dish. Thesuspension of the CORC particles/powders/micro fibers in CMC—Na solutionwas placed in an Ultra-TURRAX® T18 DIXI midi Dispersers/Homogenizershomogenizer and homogenized until the loose CORC particles/powders/microfibers are evenly distributed in the CMC—Na solution. The homogeneoussolution in the dish was transferred via a tube into LN₂ bath. TheCORC/CMC—Na suspension was instantly freezed yielding micro-porous beadsof various diameters, ranging from 0.2-9 mm, and lyophilized overnight.The micro porous-beads were further dried at room temperature undervacuum.

EXAMPLE 4 Fibrous CORC/Na—CMC Agglomerates Preparation

[0071] CORC Fibrillar is first emerged in liquid nitrogen in a stainlesssteel foil pouch then the LN₂ containing pouch filled with CORCFibrillar will go through a dual wheel/roller at 6 in/min, yielding CORCpowders, micro fibers or fine particles of various length/sizes.Particles of desired sizes can be subsequently separated with sieves.CORC particles/powders/micro fibers thus prepared were placed in theCMC—Na (Aqualon® 7M8SF) solution in the crystallization dish. Thesuspension of the CORC particles/powders/micro fibers in CMC—Na solutionwas placed in homogenizer and homogenized until the loose CORCparticles/powders/micro fibers are evenly distributed in the CMC—Nasolution. The homogeneous solution in the dish was transferred via atube into Isopropanol (IPA) bath to facilitate the precipitation ofCORC/CMC—Na composite. Excess amount of (80-95%) of IPA was removed fromthe precipitated CORC/CMC—Na composite, then the CORC/CMC—Na compositewas instantly freezed yielding fibrous agglomerates of various form andlyophilized overnight. The fibrous agglomerates were further dried atroom temperature under vacuum.

EXAMPLE 5 Hemostatic Performance of Different Materials in PorcineSplenic Incision Model

[0072] A porcine spleen incision model was used for hemostasisevaluation of different materials. The materials were cut into 2.5cm×1.5 cm rectangles or used as prepared by methods described in theexamples above. A linear incision of 1.5 cm with a depth of 0.3 cm wasmade with a surgical blade on a porcine spleen. After application of thetest article, digital tamponade was applied to the incision for 2minutes. The hemostasis was then evaluated. Additional applications ofdigital tamponade for 30 seconds each time were used until completehemostasis was achieved. Fabrics failing to provide hemostasis within 12minutes were considered to be failures. Table 1 lists the results of theevaluation. TABLE 1 Hemostatic performance of different materialsPercent of test samples to achieve hemostasis within the time period 0-22-3 3-4 4-5 <12 Maintenance of Material (min) (min) (min) (min) (min)Hemostasis Surgicel Nu-Knit ®  0%  0% 100% Re-bleeding absorbablehemostat occurred after 4 min Example 1a patch 100% No Re-bleedingoccurred Example 1b patch 100% No Re-bleeding occurred Example 1c patch100% Re-bleeding occurred Example 2 patch 100% No Re-bleeding occurredExample 3  80% 100% No CORC/Na-CMC Re-bleeding Micro porous-beadsoccurred Example 4 Fibrous 100% No agglomerates Re-bleeding occurredSurgical gauze 0% Re-bleeding occurred immediately after

We claim:
 1. A composition, comprising: biocompatible, oxidizedcellulose particles having an average designated nominal particle sizeof from about 0.035 to about 4.35 mm; and a biocompatible, porouswater-soluble or water-swellable polysaccharide binder component;wherein said composition is suitable for use in a hemostatic device. 2.The composition of claim 1 wherein the oxidized cellulose is selectedfrom the group consisting of carboxylic-oxidized cellulose oraldehyde-oxidized cellulose.
 3. The composition of claim 2 wherein saidwater-soluble or water-swellable polysaccharide is selected from thegroup consisting of methylcellulose, hydroxyalkyl cellulose, salts ofcarboxymethyl cellulose, carboxymethyl cellulose and carboxyethylcellulose.
 4. The composition of claim 2 wherein said water-soluble orwater-swellable polysaccharide is sodium carboxymethyl cellulose.
 5. Thecomposition of claim 1 wherein the weight ratio of said water-soluble orwater-swellable polysaccharide to said oxidized cellulose particles isfrom about 1:99 to about 20:80.
 6. The composition of claim 4 whereinthe weight ratio of said sodium carboxymethyl cellulose to said oxidizedcellulose particles is from about 3:97 to about 10:90.
 7. Thecomposition of claim 6 wherein said particles comprise fibers.
 8. Thecomposition of claim 7 wherein said fibers have an average designatednominal particle size of from about 0.68 to about 4.35 mm.
 9. Thecomposition of claim 1 comprising a sponge having said oxidizedcellulose particles dispersed through said binder component.
 10. Thecomposition of claim 1 comprising an agglomerate of said oxidizedcellulose particles and said binder component.
 11. A hemostatic devicecomprising a composition suitable for use therein, said compositioncomprising: biocompatible, oxidized cellulose particles having anaverage designated nominal particle size of from about 0.035 to about4.35 mm; and a biocompatible, porous water-soluble or water-swellablepolysaccharide binder component.
 12. The hemostatic device of claim 11wherein the oxidized cellulose is selected from the group consisting ofcarboxylic-oxidized regenerated cellulose or aldehyde-oxidizedcellulose.
 13. The hemostatic device of claim 12 wherein saidwater-soluble or water-swellable polysaccharide is selected from thegroup consisting of methylcellulose, hydroxyalkyl cellulose, salts ofcarboxymethyl cellulose, carboxymethyl cellulose and carboxyethylcellulose.
 14. The hemostatic device of claim 12 wherein saidwater-soluble or water-swellable polysaccharide is sodium carboxymethylcellulose.
 15. The hemostatic device of claim 11 wherein the weightratio of said water-soluble or water-swellable polysaccharide to saidoxidized cellulose is from about 1:99 to about 20:80.
 16. The hemostaticdevice of claim 4 wherein the weight ratio of said sodium carboxymethylcellulose to said oxidized cellulose is from about 3:97 to about 10:90.17. The hemostatic device of claim 16 wherein said particles comprisefibers.
 18. The hemostatic device of claim 17 wherein said fibers havean average designated nominal particle size of from about 0.68 to about4.35 mm.
 19. The hemostatic device of claim 11 comprising a spongehaving said oxidized cellulose particles dispersed through said bindercomponent.
 20. The hemostatic device of claim 11 comprising anagglomerate of said oxidized cellulose particles and said bindercomponent.
 21. The hemostatic device of claim 11 comprising saidcomposition in the form of a powder, a patch, a plug, a slurry and apaste.
 22. A composition suitable for use in a hemostatic device, saidcomposition produced according to the steps of: providing a polymersolution having a water-soluble or water-swellable polysaccharidepolymer dissolved in a suitable solvent therefore, providingbiocompatible, oxidized cellulose particles having an average designatednominal size from about of 0.035 to about 4.35 mm, contacting saidpolymer solution with said oxidized cellulose particles under conditionseffective to disperse said oxidized cellulose particles substantiallyhomogenously throughout said polymer solution to form a substantiallyhomogenous dispersion, subjecting said polymer solution having saidparticles dispersed throughout to conditions effective to solidify saidsubstantially homogenous dispersion; and removing said solvent from thesolidified dispersion, thereby forming said composition comprising saidparticles and a porous, water-soluble or water-swellable polysaccharidepolymer binder component.
 23. A process for making a composition usefulin a hemostatic device, comprising: providing a polymer solution havinga water-soluble or water-swellable polysaccharide polymer dissolved in asuitable solvent therefore, providing biocompatible, oxidized celluloseparticles having an average designated nominal size from about of 0.035to about 4.35 mm, contacting said polymer solution with said oxidizedcellulose particles under conditions effective to disperse said oxidizedcellulose particles substantially homogenously throughout said polymersolution to form a substantially homogenous dispersion, subjecting saidpolymer solution having said particles dispersed throughout toconditions effective to solidify said substantially homogenousdispersion; and removing said solvent from the solidified dispersion,thereby forming said composition comprising said particles and a porous,water-soluble or water-swellable polysaccharide polymer bindercomponent.
 24. The process of claim 23 wherein said oxidized cellulosecomprise carboxylic-oxidized regenerated cellulose.
 25. The process ofclaim 23 wherein said water-soluble or water-swellable polysaccharidepolymer is selected from the group consisting of methylcellulose,hydroxyalkyl cellulose, salts of carboxymethyl cellulose, carboxymethylcellulose and carboxyethyl cellulose.
 26. The process of claim 25wherein said polymer is sodium carboxymethyl cellulose.
 27. The processof claim 26 wherein the weight ratio of said sodium carboxymethylcellulose to said fibers or beads is from about 1:99 to about 20:80. 28.The process of claim 26 wherein the weight ratio of said sodiumcarboxymethyl cellulose to said fibers or beads is from about 3:97 toabout 10:90.